The inhibition of cardiac Na ion,K ion-ATPase and sodium-pump activity by cardiac glycosides or by monovalent cations appears to be intimately related to the positive inotropic action of these agents. The events which connect sodium-pump inhibition to the enhanced cardiac contractile force will be studied by first elucidating the influence of sodium-pump inhibition on the dynamic changes which occur in intracellular cation concentrations during each cycle of contraction and relaxation and subsequently determining the influences of such ionic alterations on calcium turnover. The magnitude of the influence of direct action of cardiac glycosides on the central nervous system to affect sympathetic outflow will be estimated. Additionally, the nature of the molecular interactions between cardiac glycosides and inotropic and toxic "receptors" for these agents, and the factors and agents which modify such interactions will be studied using an in vitro model. Finally, attempts will be made to modify chemical structure of cardiac glycosides so that it occupies cardiotonic steroid binding sites on Na ion,K ion-ATPase without affecting the enzyme activity. BIBLIOGRAPHIC REFERENCES: L.C. Weaver, T. Akera and T. M. Brody: Digoxin toxicity: Primary sites of drug action on the sympathetic nervous system. Fed. Proc. 34: 745, 1975; D. Ku, T. Akera, T. Tobin and T.M. Brody: Comparative species-studies on the effect of monovalent cations and ouabain on cardiac Na ion,K ion-ATPase and contractile force. Fed. Proc. 34:792, 1975.